Antimicrobials 1

• Narrow-spectrum drugs


  Generally preferred to broad-spectrum drugs
• Mechanisms of action of drugs

  • Inhibit bacterial cell wall synthesis or activate enzymes that disrupt the cell wall (e.g. penicillins and cephalosporins)
  • Increase cell membrane permeability (e.g. amphotericin B)
  • Cause lethal inhibition of bacterial protein synthesis (aminoglycosides)
  • Cause nonlethal inhibition of bacterial protein synthesis (e.g. tetracyclines)
  • Inhibit bacterial synthesis of DNA and RNA or disrupt DNA function (e.g. rifampin, metronidazole, fluoroquinolones)
  • Disrupt specific biochemical reactions (antimetabolites like trimethoprim and sulfonamides)
  • Suppress viral replication (inhibit enzymes like DNA polymerase, reverse transcriptase, protease, integrase, or neuraminidase)
• Over time, an organism that had once been highly sensitive to an antibiotic may become less susceptible, or it may lose drug sensitivity entirely
• Acquired resistance is of great concern as it can render currently effective drugs useless, thereby creating a clinical crisis and a constant need for new antimicrobial agents
• Organisms for which drug resistance is currently a serious problem

  • Enterococcus faecium
  • Staphylococcus aureus
  • Enterobacter species
  • Pseudomonas aeruginosa
  • Acinetobacter baumannii
  • Klebsiella species
  • Clostridium difficile
• Mechanisms for microbes to resist drugs

  • Decrease the concentration of a drug at its site of action
  • Alter the structure of drug target molecules
  • Produce a drug antagonist
  • Cause drug inactivation
• NDM-1 gene


  Codes for a powerful form of β-lactamase that can inactivate essentially all β-lactam antibiotics
• The DNA segment that contains the NDM-1 gene also contains genes that code for additional resistance determinants, including drug efflux pumps, and enzymes that can inactivate other important antibiotics
• Spontaneous mutations


  Produce random changes in a microbe's DNA, resulting in a gradual increase in resistance
• Conjugation


  A process by which extrachromosomal DNA is transferred from one bacterium to another, allowing for transfer of resistance
• How antibiotics promote resistance

  • Microbes secrete compounds that are toxic to other microbes
  • Microbes within a given ecologic location compete with each other for available nutrients, and antibiotics kill off sensitive organisms allowing resistant ones to grow
• Broad-spectrum antibiotics kill more competing organisms than do narrow-spectrum drugs, therefore broad-spectrum agents do the most to facilitate emergence of resistance
• The more antibiotics are used, the faster drug-resistant organisms emerge
• Antibiotics promote emergence of resistant pathogens and also promote overgrowth of normal flora that possess mechanisms for resistance
• Health care−associated infections (HAIs) are among the most difficult to treat due to the high levels of drug resistance in hospitals
• Superinfection


  A new infection that appears during the course of treatment for a primary infection, due to antibiotics eliminating the inhibitory influence of normal flora
• Focus areas to decrease antibiotic resistance


  • Surveillance, Prevention and Control of Antimicrobial Resistant Infections
  • Research
  • Regulatory Pathways for New Products
  • Product Development
• Factors to consider when choosing an antibiotic

  • Identity of the infecting organism
  • Drug sensitivity of the infecting organism
  • Host factors like site of infection and status of host defenses
• Gram stain


  A quick, simple, and versatile technique for identifying microorganisms
• Polymerase chain reaction (PCR) test


  A relatively new method that can detect very low titers of bacteria and viruses
• Before sensitivity testing can be done, the microbe must first be identified so that it can be tested for sensitivity to the appropriate drugs
• Minimum inhibitory concentration (MIC)


  The drug concentration required to inhibit the growth of the infecting organism
• Potential interactions when using two antibiotics together

  • Additive (equal to the sum of the effects)
  • Potentiative/synergistic (greater than the sum of the effects)
  • Antagonistic
• The most common indication for using multiple antibiotics is initial therapy of severe infection of unknown etiology, especially in the neutropenic host
• Use of multiple antibiotics has several drawbacks, including increased risk for toxic and allergic reactions, possible antagonism of antimicrobial effects, increased risk for superinfection, selection of drug-resistant bacteria, and increased cost
• Approved indications for antimicrobial prophylaxis

  • Surgery
  • Bacterial endocarditis
  • Neutropenia
  • Recurrent UTIs
  • Influenza
• One in every three outpatient antibiotic prescriptions is either inappropriate or entirely unnecessary
• Ways antibiotics are misused

  • Treatment of viral infections
  • Treatment of fever of unknown origin
  • Improper dosage (too low or too high)
  • Treatment in the absence of information on infecting organism
  • Omission of surgical drainage
• Penicillins


  Belong to the beta-lactam family of antibiotics, as they contain a beta-lactam ring in their structure
• Antimicrobial therapy assessment


  1. Monitoring clinical responses

  2. Monitoring laboratory results

  3. Frequency of monitoring is directly proportional to the severity of infection
• Indicators of successful antimicrobial therapy

  • Reduction of fever
  • Resolution of signs and symptoms related to the affected organ system (e.g., improvement of breath sounds in patients with pneumonia)
• Various laboratory tests are used to monitor treatment
• Serum drug levels monitoring

  To ensure that levels are sufficient for antimicrobial effects and to avoid toxicity from excessive levels
• Success of therapy


  Disappearance of infectious organisms from posttreatment cultures
• Cultures may become sterile within hours of the onset of treatment (as may happen with urinary tract infections), or they may not become sterile for weeks (as may happen with tuberculosis)
• Beta-lactam antibiotics


  Weaken the cell wall, causing bacteria to take up excessive amounts of water and rupture
• Penicillins


  • Can be narrow or broad spectrum, therefore they can be used to treat infections caused by a wide variety of bacteria
  • Practically ideal antibiotics because they are active against a variety of bacteria and their direct toxicity is low
  • Allergic reactions are the principal adverse effects
  • Widely prescribed
• Because they have a β-lactam ring in their structure, the penicillins are known as β-lactam antibiotics
• β-lactam family


  • Penicillins
  • Cephalosporins
  • Carbapenems
  • Aztreonam
  • Imipenem
  • Meropenem
  • Ertapenem
• Mechanism of action of β-lactam antibiotics

  Disruption of the bacterial cell wall